Some known antimicrobial agents inhibit bacterial DNA synthesis by acting on DNA gyrase and topoisomerase. DNA gyrase and topoisomerase IV are both type II topoisomerases, consisting of two protein subunits that act as A2B2 heterotetramers. The ATPase domain resides on one polypeptide of the dimer (GyrB in DNA gyrase, ParE in topoisomerase IV), while the DNA cleavage core lies on a second polypeptide (GyrA in DNA gyrase, ParC in topoisomerase IV).
Some antibacterial inhibitors of gyrase including aminocoumarins such as novobiocin, function as competitive inhibitors of energy transduction of DNA gyrase by binding to the ATPase active site in GyrB. In contrast, the quinolone antibiotics such as nalidixic acid, ciprofloxacin and moxifloxacin, preferentially bind these enzymes at the cleavage core (GyrA and ParC) and prevent DNA replication and thus halt cell division in both Gram positive and Gram negative bacteria. Although first site resistance mutations generally occur in gyrA, mutations in gyrB also have been shown to reduce susceptibility to these known quinolones.
Bacterial DNA synthesis inhibitors (e.g. fluoroquinolones) have been used to treat primarily Gram-negative infections and have historically achieved good clinical outcomes. A wealth of knowledge exists for the quinolone class of compounds, including bioavailability, tissue distribution, PK/PD relationships and photoxicity. Structurally, quinolone antibiotics possess a bicyclic (ciprofloxacin and moxifloxacin) or tricyclic ring structure (levofloxacin) with an aryl side chain containing an acyclic ring incorporating an amine functionality. Most of the known fluoroquinolones possess a keto-acid functionality, either a carboxylic acid (ciprofloxacin and moxifloxacin, levofloxacin, the monocyclic and bicyclic 2-pyridone and 4-pyridones), hydroxylamine (quinazolinediones and tricyclic isoquinolones), or a hydrazine (quinazolinediones) group, which relate to DNA gyrase and topoisomerase activity and presumably bind to a divalent cation in the activated complex. Most inhibitors also possess an amine functional group attached to the core heterocycle, making these compounds zwitterionic in nature. Monocyclic 2-pyridone and 4-pyridone (e.g., Ro-13-5478) inhibitors possess this amine functionality attached to a phenyl group. The zwitterionic nature of these inhibitors relate to the permeation of these compounds into the Gram-negative cell using porin channels.
Quinolone antibiotics have been highly effective, but wide-scale deployment of the current drugs, including usage of the effective second generation quinolones that have become generic drugs (e.g., ciprofloxacin), threatens their future long-term utility. Quinolone resistance is already rising in both hospitals and the community at large. See Tessier and Nicolau, Antimicrob. Agents Chemother. 54(6), 2887-89 (2013). To combat such resistant strains, new gyrase inhibitors that are active against bacteria resistant to current quinolones, especially antibiotics targeting multi-drug resistant (MDR) Gram-negative pathogens that retain efficacy against bacteria that are resistant to known quinolones, would address an important unmet medical need.
The present invention relates to antibacterial compounds having activity against both wild-type and quinolone-resistant bacteria. It relates particularly to compounds having activity against quinolone-resistant Gram-negative bacteria, including multi-drug resistant (MDR) strains of e.g. Pseudomonas aeruginosa, as well as antibacterial activity against wild-type and quinolone-resistant Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The present invention also relates to compounds with selectivity between bacterial topoisomerase IV and DNA gyrase enzyme inhibition compared to human topoisomerase II enzyme inhibition, providing a therapeutic index consistent with in vivo use to treat bacterial infections in humans.